Phenacyl-type esters of PGE-types compounds

ABSTRACT

Phenacyl-type esters of PGE 2 , PGE 1 , and 13,14-dihydro-PGE 1  and their 15-methyl, 16,16-dimethyl, and 17-phenyl analogs, including the respective 15(R)epimers, are disclosed, represented by the formula ##STR1## wherein M is ##STR2## wherein R 3  is hydrogen or methyl; wherein Q is ##STR3## wherein each of R 4  and R 5  is hydrogen or methyl, being the same or different, or ##STR4## wherein the moiety--C t  H 2t  -- represents a valence bond or alkylene of one to 10 carbon atoms, inclusive, with one to 7 carbon atoms, inclusive, between ##STR5## and the phenyl ring; wherein R 1  is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl; wherein R 2  is hydrogen or benzoyl; and wherein (a) X is --CH 2  CH 2  -- or trans--CH═CH-- and Y is --CH 2  CH 2  --, or (b) X is trans--CH═CH-- and Y is cis--CH═CH--. The products are useful for the same pharmacological and medical purposes as the corresponding prostaglandins and analogs, and are also useful as a means for obtaining highly purified products.

BACKGROUND OF THE INVENTION

This invention relates to novel ester derivitives of prostaglandin E₂(hereinafter identified as "PGE₂ "), PGE₁, and 13,14-dihydro-PGE₁ andtheir 15-methyl, 16-(or 16,16-di)-methyl, and phenyl-substitutedanalogs, including the respective 15(R)epimers, and to processes forproducing them.

PGE₂ is represented by the formula: ##STR6## A systematic name for pGE₂is7-{3α-hydroxy-2β-[(3S)-3-hydroxy-trans-1-octenyl]-5-oxo-1.alpha.-cyclopentyl}-cis-5-heptenoicacid. PGE₂ is known to be useful for a variety of pharmacological andmedical purposes, for example labor induction and abortion in pregnantanimals, including humans, menstrual regulation in both pregnant andnon-pregnant animals, including humans, reduction and control of gastricsecretion, and as a hypotensive agent to reduce blood pressure inmammals, including humans. See Bergstrom et al., Pharmacol. Rev. 20, 1(1968) and references cited therein. As to racemic PGE₂, see for exampleW. P. Schneider, Chem. Commun. 304 (1969).

The 15(S)-15-methyl-PGE₂ analog and its 15(R) epimer are represented bythe formula: ##STR7## wherein M' is ##STR8## following the usualconvention wherein broken line attachment of hydroxy to the side chainat carbon 15 indicates the natural or "S" configuration and solid lineattachment of hydroxy indicates the epi or "R" configuration. See forexample Nugteren et al., Nature 212, 38 (1966) and Cahn, J. Chem. Ed.41, 116 (1964). The 15(S)-15-methyl- and 15(R)-15-methyl-PGE₂ analogs intheir optically active and racemic forms are known. See for example U.S.Pat. No. 3,728,382. These analogs are also useful for theabove-described pharmacological purposes.

The 16-(or 16,16-di)methyl-PGE₂ analogs and their 15(R) epimers arerepresented by the formula: ##STR9## wherein M is ##STR10## wherein R₃is hydrogen or methyl, and wherein each of R₄ and R₅ is hydrogen ormethyl, being the same or different. These 16-methyl- and16,16-dimethyl-PGE₂ analogs and their 15(R) epimers in their opticallyactive and racemic forms are available or can be prepared by methodsknown in the art. See for example German Pat. No. 2,217,044, DerwentFarmdoc No. 71483T.

The phenyl-substituted PGE₂ analogs and their 15(R) epimers arerepresented by the formula: ##STR11## wherein M is ##STR12## wherein R₃is hydrogen or methyl, and wherein C_(t) H_(2t) represents a valencebond or alkylene of one to 10 carbon atoms, inclusive, with one to 7carbon atoms, inclusive, between ##STR13## and the phenyl ring. Thesesubstituted analogs and their 15(R) epimers in their optically activeand racemic forms are available or can be prepared by methods known inthe art. See for example German Pat. No. 2,154,309, Derwent Farmdoc Nol31279T.

PGE₁ is represented by the formula: ##STR14## and the PGE₁ analogs arerepresented similarly to the PGE₂ analogs above except that cis--CH═CH--in the carboxy acid side chain of formulas II, III, and IV is replacedby --CH₂ CH₂ --. These PGE₁ compounds are available or are prepared bymethods known in the art. See for example E. J. Corey et al., J. Am.Chem. Soc. 90, 3245 (1968) and 92, 2586 (1970); U.S. Pat. nos.3,069,322, and 3,728,382, 3,598,858, J. E. Pike et al., J. Org. Chem.34, 3552 (1969); G. L. Bundy et al., Ann. N.Y. Acad. Sci. 180, 76(1971); and German Pat. No. 2,154,309, Derwent Farmdoc No. 31279T.

13,14-Dihydro-PGE₁ is represented by the formula: ##STR15## and the13,14-dihydro-PGE₁ analogs are represented similarly to the PGE₂ analogsabove except that cis--CH═CH-- in the carboxy acid side chain andtrans--CH═CH-- in the alkyl-terminated side chain of formulas II, III,and IV are replaced by --CH₂ CH₂ --. These 13,14-dihydro-PGE₁ compoundsare available or are prepared by methods known in the art. See forexample U.S. Pat. Nos. 3,711,528, 3,728,382, 3,776,938; and German Pat.No. 2,154,309, Derwent Farmdoc No. 31279T.

All of the above prostaglandin-type compounds are known to be useful fora variety of pharmacological and medical purposes, and the esters ofthis invention are useful for the same purposes.

Esters of the above compounds are known, wherein the hydrogen atom ofthe carboxyl group is replaced by a hydrocarbyl or substitutedhydrocarbyl group. Among these are the methyl ester of PGE₂ (B.Samuelsson, J. Biol. Chem. 238, 3229 (1963)), the methyl ester of15-methyl-PGE₂ (E. W. Yankee et al., J. Am. Chem. Soc. 94, 3651 (1972)),the methyl ester of 13,14-dihydro-PGE₁ (U.S. Pat. No. 3,598,858), thedecyl ester of PGE₂ (Belgian Pat. No. 765,732, Derwent Farmdoc No.67580S), the 2-phenoxyethyl ester of PGE₂ (Belgian Pat. No. 766,294,Derwent Farmdoc No. 39011T), the phenyl and alkyl-phenyl esters of PGE₂(British Spec. No. 1,282,661, Derwent Farmdoc No. 67438R), thep-(1,1-3,3-tetramethyl-butyl)-phenyl ester of PGE₂, the α (andβ-)-naphthyl ester of PGE₂, and the 5,6,7,8-tetrahydro-2-naphthyl esterof PGE₂ (Belgian Pat. No. 775,106, Derwent Farmdoc No. 33705T) themethyl ester of 16,16-dimethyl-PGE₂ (German Pat. No. 2,217,044, Derwent71483T), and the methyl and phenyl esters of17-phenyl-18,19,20-trinor-PGE₂ (German Pat. No. 2,154,309, Derwent31279T).

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel ester derivatives ofPGE₂, PGE₁, and 13,14-dihydro-PGE₁ and their 15-methyl, 16-(or16,16-di)methyl, and phenyl-substituted analogs, including therespective 15(R) epimers. It is a further purpose to provide each estersin a free-flowing crystalline form. It is still a further purpose toprovide novel processes for preparing these esters.

The presently described phenacyl-type esters include compoundsrepresented by the generic formula: ##STR16## wherein M is ##STR17##wherein R₃ is hydrogen or methyl; wherein Q is ##STR18## wherein each ofR₄ and R₅ is hydrogen or methyl, being the same or different, or##STR19## wherein the moiety C_(t) H_(2t) - represents a valence bond oralkylene of one to 10 carbon atoms, inclusive, with one to 7 carbonatoms, inclusive, between ##STR20## and the phenyl ring; wherein R₁ isphenyl, p-bromophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl, or2-naphthyl; wherein R₂ is hydrogen or benzoyl; and wherein (a) X is--CH₂ CH₂ -- or trans--CH═CH-- and Y is --CH₂ CH₂ --, or (b) X istrans--CH═CH-- and Y is cis--CH═CH--.

Thus, in the presently described esters, the group ##STR21## isexemplified by: ##STR22##

For example, PGE₂, phenacyl ester, is represented by formula VI when Mis ##STR23## X is trans--CH═CH--, Y is cis--CH═CH--, and ##STR24## is A,i.e. ##STR25## and is conveniently identified herein as the PGE₂ esterof formula VI-A. Racemic compounds are designated by the prefix"racemic" or "dl;" when that prefix is absent, the intent is todesignate an optically active compound. For example, racemic15-methyl-PGE₁, p-benzamidophenacyl ester, corresponds to formula VIwherein M is ##STR26## X is trans--CH═CH--, Y is --CH₂ CH₂ --, and##STR27## including of course not only the optically active isomerrepresented by formula VI but also its mirror image.

The novel formula-VI compounds and corresponding racemic compound ofthis invention are each useful for the same purposes as described abovefor PGE₂ and are used for those purposes in the same manner known in theart, including oral, sublingual, buccal, rectal, intravaginal,intrauterine, or topical administration.

For many applications these novel prostaglandin esters which I haveobtained from certain specified phenacyl-type halides have advantagesover the corresponding known prostaglandin compounds. Thus, thesephenacyl-type esters are surprisingly stable compounds havingoutstanding shelf-life and thermal stability. In contrast to the acidform of these prostaglandins, these esters are not subject toacid-catalyzed decomposition either by elimination of water or byepirmerization. Thus these compounds have improved stabilty either insolid, liquid, or solution form. In oral administration these estershave shown surprisingly greater efficacy than the corresponding freeacids or lower alkyl esters, whether because of longer duration ofbiological activity or because of improved lipophilicity and absorptionis not certain. These esters offer a further advantage in that they havelow solubility in water and the body fluids and are therefore retainedlonger at the site of administration.

A particularly outstanding advantage of many of these phenacyl-typeesters is that they are obtained in free-flowing crystalline form,generally of moderately high melting point, in the range 50°-130° C.This form is especially desirable for ease of handling, administering,and purifying. These crystals are highly stable, for example showingpractically no decomposition at accelerated storage tests, in comparisonwith liquid alkyl esters or the free acids. This quality is advantageousbecause the compound does not lose its potency and does not becomecontaminated with decomposition products.

These crystalline esters also provide a means of purifying PGE₂,PGE₁,13,14-dihydro-PGE₁, and their 15-methyl, 16-(or 16,16-di)methyl, orphenyl-substituted analogs, including the respective 15(R) epimers,which are first converted to one of these esters, crystallized andrecrystallized until pure, and then recovered as the free acid. Onemethod of recovering the free acid is by enzymatic hydrolysis of theester, for example with a lipase. See German Pat. No. 2,242,792, DerwentFarmdoc No. 23047U.

A p-iodophenacyl ester of 15(S)-15-methyl-PGF₂α was useful for X-raycrystallographic structure determination, E. W. Yankee et al., J. Am.Chem. Soc. 94, 3651 (1972). Various phenacyl esters have been useful forcharacterizing aliphatic acids because of their sharp melting points,Shriner and Fuson, "Systematic Identification of Organic Compounds", 3rdEd., pp. 154-157 (1948).

Especially preferred of the novel compounds of this invention are thosecompounds which are in free-flowing crystalline form, for example:

phenacyl ester of PGE₂

p-bromophenacyl ester of PGE₂

p-phenylphenacyl ester of PGE₂

p-nitrophenacyl ester of PGE₂

p-benzamidophenacyl ester of PGE₂

p-naphthoylmethyl ester of PGE₂

α-benzoylphenacyl ester of PGE₂

p-phenylphenacyl ester of 15(S)-15-methyl-PGE₂

p-nitrophenacyl ester of 15(S)-15-methyl-PGE₂

p-nitrophenacyl ester of 17-phenyl-18,19,20-trinor-PGE₂

p-phenylphenacyl ester of PGE₁

p-phenylphenacyl ester of 16,16-dimethyl-PGE₁

p-phenylphenacyl ester of 17-phenyl-PGE₁

p-phenylphenacyl ester of 13,14-dihydro-18,19,20-trinor-PGE₁

The phenacyl-type esters of PGE₂, PGE₁, 13,14-dihydro-PGE₁ and their15-methyl, 16-(or 16,16-di)methyl, or phenyl-substituted analogs,including the respective 15(R) epimers encompassed by formula VI wherein##STR28## is defined by ester groups A through G are produced by thereactions and procedures described and exemplified hereinafter. Forconvenience, the prostaglandin or prostaglandin analog is referred to as"the PG compound." the term "phenacyl" is used in a generic sense,including also substituted phenyl and naphthyl derivatives.

Various methods are available for preparing these esters. Thus, by onemethod, the PG compound is converted to a sodium salt by method known inthe art and reacted with an appropriate phenacyl halide in a solvent.

Preferred, however, is the method of simply mixing the PG compound witha phenacyl halide, preferably the bromide, and a tertiary amine in asolvent and letting the reaction proceed at room temperature (about 20°to 30° C.). The course of the reaction is readily followed by samplingthe mixture and subjecting the samples to thin layer chromatogrphy,usually being complete within 0.25-4.0 hr. Thereafter the reactionmixture is worked up to yield the ester following methods describedherein or known in the art, for example the product being purified bysilica gel chromatography.

Examples of the phenacyl-type halides useful for this purpose are:phenacyl bromide, p-bromophenacyl bromide, p-phenylphenacyl bromide,p-nitrophenacyl bromide, p-benzamidophenacyl bromide,2-bromo-2'-acetonaphthone, and 2-bromo-1,3-diphenyl-1,3-propanedione. Inusing these reagents the usual precautions are taken to avoid theirlachrymatory effects.

Examples of suitable tertiary amines are triethylamine,diethylmethylamine, diisopropylethylamine, dimethylisobutylamine, anddimethylaniline.

Examples of suitable solvents are acetonitrile, dioxane, andtetrahydrofuran, N,N-dimethylformamide, and dimethylsulfoxide.

The phenacyl halide is preferably used in equivalent amounts or inexcess to insure that all of the PG compound is converted to ester.Excess phenacyl halide is separated from the product by methodsdescribed herein or known in the art, for example by chromatography.

Solid esters are converted to a free-flowing crystalline form oncrystallization from a variety of solvents, including ethyl acetate,tetrahydrofuran, methanol, ethanol, and acetone, by cooling orevaporating a saturated solution of the ester in the solvent or byadding a miscible non-solvent such as diethyl ether, hexane, or water.The crystals are then collected by conventional techniques, e.g.filtration or centrifugation, washed with a small amount of solvent, anddried under reduced pressure. They may be dried in a current of warmnitrogen or argon, or by warming up to about 75° C., taking care not toexceed the melting point. Although the crystals are normally pure enoughfor many applications, they may be recrystallized by the same generaltechniques to achieve improved purity after each recrystallization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples.

All temperatures are in degrees centrigrade.

Silica gel chromatography, as used herein, is understood to includechromatography on a column packed with silica gel, elution, collectionof fractions, and combination of those fractions shown by thin layerchromatography (TLC) to contain the desired product free of startingmaterial and impurities.

"TLC", herein, refers to thin layer chromatography.

EXAMPLE 1 PGE₂, Phenacyl Ester (Formula VI-A wherein M is ##STR29## Q isn-pentyl, X is trans-CH═CH--, and Y is cis--CH═CH--)

A mixture of PGE₂ (0.50 g.), phenacyl bromide (0.440 g.) and 0.37 ml. ofdiisopropylethylamine in 10 ml. of acetonitrile is left standing for onehour at about 25° C. The mixture is diluted with 200 ml. of ethylacetate and extracted with aqueous 0.1 N. phosphate buffer at pH 7.5 andthen water. The organic phase is dried over sodium sulfate andconcentrated under reduced pressure to a crude residue. The residue issubjected to silica gel chromatography, eluting with ethylacetate-hexane (1:1) followed by ethyl acetate. The residue obtained byconcentration of selected fractions is crystallized from ethylacetate-hexane as the title compound, white free-flowing crystals, 0.510g., m.p. 57.3°-58.8°, having R_(f) 0.65 (TLC on silica gel in ethylacetate).

EXAMPLE 2 PGE₂, p-Bromophenacyl Ester (Formula VI-B wherein M is##STR30## Q is n-pentyl, X is trans--CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.50 g. of PGE₂, 0.80 g.of p-bromophenacyl bromide, and 0.37 ml. of diisopropylethylamine in 10ml. acetonitrile kept for 2 hrs. at about 25° C., there is obtained acrude residue. This residue is subjected to silica gel chromatography,eluting with ethyl-acetate-hexane (1:1) followed by ethylacetate. Theresidue obtained by concentration of selected fractions is crystallizedfrom ethyl acetate-hexane as the title compound, white free-flowingcrystals, 0.628 g., m.p. 83.3°-87.5° C., having R_(f) 0.4 (TLC on silicagel in ethylacetate-hexane (7:3)).

EXAMPLE 3 PGE₂, p-Phenylphenacyl Ester (Formula VI-C wherein M is##STR31## Q is n-pentyl, X is trans--CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.242 g. of PGE₂, 0.720g. of p-phenylphenacyl bromide, and 0.40 ml. of diisopropylethylamine,there is obtained a crude residue. This residue is subjected to silicagel chromatography, eluting with 100 ml. of ethyl acetate-hexane (1:3)followed by 100 ml. of ethyl acetate-hexane (1:1), 200 ml. of ethylacetate and finally 200 ml. of ethyl acetate-acetone (3:2). The residueobtained by concentration of selected fractions is crystallized fromethyl acetate-hexane as the title compound, white free-flowing crystals,0.328 g., m.p. 98.6°-100.9°, having R_(f) 0.4 (TLC on silica gel inethyl acetate-hexane (4:1)).

EXAMPLE 4 PGE₂ p-Nitrophenacyl Ester (Formula VI-D wherein M is##STR32## Q is n-pentyl, X is trans-CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.100 g. of PGE₂, 0.100g. of p-nitrophenacyl bromide, and 0.100 ml. of diisopropylethylamine in10 ml. of acetonitrile for 15 min. at about 25° C., there is obtained acrude residue. This residue is subjected to silica gel chromatography,eluting with chloroform-acetonitrile (9:1). The residue obtained byconcentration of selected fractions is crystallized from ethylacetate-hexane as the title compound, white free-flowing crystals, 0.088g., m.p. 65.9°-67.2° C., having R_(f) 0.7 (TLC on silica gel inchloroform-acetonitrile (1:1)).

EXAMPLE 5 PGE₂, p-Benzamidophenacyl Ester (Formula VI-E wherein M is##STR33## Q is n-pentyl, X is trans--CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.352 g. of PGE₂, 0.410g. of p-benzamidophenacyl bromide, and 1.0 ml. of diisopropylethylaminein 20 ml. of acetonitrile held for 2 hr. at about 25° C., there isobtained a crude residue. This residue is subjected to silica gelchromatography, eluting with ethyl acetate-hexane (7:3) followed bytetrahydrofuran. The residue obtained by concentration of selectedfractions is crystallized from hot ethanol-water (1:1) as the titlecompound, white free-flowing crystals, 0.39 g., m.p. 125.8°-129.0° C.,having R_(f) 0.42 (TLC on silica gel in ethyl acetate-acetic acid(97:3)).

EXAMPLE 6 PGE₂, 2-Naphthoylmethyl Ester (Formula VI-F wherein M is##STR34## Q is n-pentyl, X is trans--CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.500 g. of PGE₂, 0.80 g.of 2-bromo-2'-acetonaphthone, and 0.37 ml. of diisopropylethylamine in10 ml. of acetonitrile kept for 2 hr. at about 25° C., there is obtaineda crude residue. This residue is subjected to silica gel chromatography,eluting with ethyl acetate-hexane (1:1) followed by ethyl acetate. Theresidue obtained by concentration of selected fractions is crystallizedfrom ethyl acetate-hexane, as the title compound, white free-flowingcrystals, 0.658 g., m.p. 64.8°-66.3° C., having R_(f) 0.4 (TLC on silicagel in ethyl acetate-hexane (7:3)).

EXAMPLE 7 PGE₂, α-Benzoylphenacyl Ester (Formula VI-G wherein M is##STR35## Q is n-pentyl, X is trans--CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.352 g. of PGE₂, 0.306g. of 2-bromo-1,3-diphenyl-1,3-propanedione, and 0.129 g. ofdiisopropylethylamine, there is obtained a crude residue. This residueis subjected to silica gel chromatography, eluting withchloroform-acetonitrile (9:1). The residue obtained by concentration ofselected fractions is crystallized from ethyl acetate-hexane as thetitle compound, white free-flowing crystals, 0.165 g., m.p.103.8°-106.5° C., having R_(f) 0.5 (TLC on silica gel inchloroformacetonitrile (7.3)).

EXAMPLE 8 15(S)-15-Methyl-PGE₂, p-Phenylphenacyl Ester (Formula VI-Cwherein M is ##STR36## Q is n-pentyl, X is trans--CH═CH--, and Y iscis--CH═CH--)

Following the procedure of Example 1 but using 0.163 g. of15-methyl-PGE₂, 0.611 g. of p-phenylphenacyl bromide, and 0.154 ml. ofdiisopropylethylamine in 12 ml. of acetonitirle, held for 1 hr. at about25° C., there is obtained a crude residue. This residue is subjected tosilica gel chromatography, eluting with ethyl acetate. The residueobtained by concentration of selected fractions is crystallized fromethyl acetate-hexane as the title compound, white free-flowing crystals,0.153 g., m.p. 90.3°-91.3° C., having R_(f) 0.7 (TLC on silica gel inethyl acetate-acetic acid (97:3)).

EXAMPLE 9 15(S)-15-Methyl-PGE₂, p-Nitrophenacyl Ester (Formula VI-Dwherein M is ##STR37## Q is n-pentyl, X is trans--CH═CH--, and Y iscis--CH═CH--)

Following the procedure of Example 1 but using 0.163 g. of15-methyl-PGE₂, 0.543 g. of p-nitrophenacyl bromide, and 0.154 ml. ofdiisopropylethylamine in 10 ml. of acetonitrile, held for one hour atabout 25° C., there is obtained a crude residue. This residue issubjected to silica gel chromatography, eluting with ethylacetate-chloroform (1:1) followed by ethyl acetate-acetone (4:1). Theresidue obtained by concentration of selected fractions, an oil, isfurther purified on a preparative TLC silica gel plate, eluting withacetone-methanol (4:1). There is obtained the title compound, apale-yellow free-flowing crystalline solid, 0.117 g., m.p. 115.8°-118.8°C., having R_(f) 0.6 (TLC on silica gel in ethyl acetate).

EXAMPLE 10 15(R)-15-Methyl-PGE₂, p-Nitrophenacyl Ester (Formula VI-Dwherein M is ##STR38## Q is n-pentyl, X is trans--CH═CH-- and Y iscis-CH═CH--)

Following the procedure of Example 1 but using 0.205 g. of15(R)-15-Methyl-PGE₂, 0.274 g. of p-nitrophenacyl bromide and 0.145 ml.of diisopropylethylamine, there is obtained a crude, viscous, brownresidue. This residue is subjected to silica gel chromatography, elutingwith chloroform-acetonitrile (1:1). The residue obtained byconcentration of selected fractions, colorless liquid, 0.290 g. is thetitle compound, a colorless liquid, 0.290 g., having R_(f) 0.5 (TLC onsilica gel in chloroform-acetonitrile (1:2)).

EXAMPLE 11 16,16-Dimethyl-PGE₂, Phenacyl Ester (Formula VI-A wherein Mis ##STR39## Q is ##STR40## X is trans--CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.190 g. of16,16-dimethyl-PGE₂, 0.099 g. of α-bromoacetophenone, and 0.065 g. ofdiisopropylethylamine in 15 ml. of acetonitrile, stirred for one hour atabout 25° C., there is obtained a crude residue. This residue isdissolved in 20 ml. of acetonitrile, mixed with 100 ml. of 0.1 N. citricacid buffer at pH 2.5, and extracted with 100 ml. of ethyl acetate. Theorganic phase is dried and concentrated to yield the title compound, alight yellow gum, having mass spectral peaks at 627, 552, 543, 537, 453,399, 227, 105, and 77, and having R_(f) 0.64 (TLC on silica gel in ethylacetate-acetic acid (97:3)).

EXAMPLE 12 16,16-Dimethyl-PGE₂, p-Phenylphenacyl Ester (Formula VI-Cwherein M is ##STR41## X is trans--CH═CH--, and Y is cis--CH═CH--)

Following the procedure of Example 1 but using 0.190 g. of16,16-dimethyl-PGE₂, 0.550 g. of 2-bromo-4'-phenylacetophenone, and0.297 g. of diisopropylamine in 15 ml. of acetonitrile, stirred for onehour at about 25° C., there is obtained a crude residue. This residue issubjected to silica gel chromatography, eluting with hexane followed byethyl acetatehexane (1:1). The residue obtained by concentration ofselected fractions is the title compound, a light yellow gum, havingmass spectral peaks at 619, 529, 497, 475, 407, and 181, and havingR_(f) 0.73 (TLC on silica gel in ethyl acetate-acetic acid (97:3))

EXAMPLE 13 17-Phenyl-18,19,20-trinor-PGE₂, p-Nitrophenacyl Ester,(Formula VI-D wherein M is ##STR42## X is trans--CH═CH--, and Y iscis--CH═CH--)

Following the procedure of Example 1 but using 0.210 g. of17-phenyl-18,19,20-trinor-PGE₂, 0.275 g. p-nitrophenacyl bromide, and0.146 ml. of diisopropylethylamine, there is obtained a crude, lightbrown, viscous residue. This residue is subjected to silica gelchromatography, eluting with chloroform-acetonitrile (1:1). The residueobtained by concentration of selected fractions is a colorlesssemisolid, which is crystallized from 5 ml. ethylacetate by dilutionwith 5 ml. hexane to yield the title compound, white free-flowingcrystals, 0.250 g., m.p. 74.7°-76.5° C., having R_(f) 0.45 (TLC onsilica gel in chloroform-acetonitrile (1:1)).

EXAMPLE 14 PGE₁, p-Phenylphenacyl Ester (Formula VI-C wherein M is##STR43## Q is n-pentyl, X is trans--CH═CH--, and Y is --CH₂ CH₂ --)

A mixture of PGE₁ (0.555 g.), p-phenylphenacyl bromide (0.731 g.) and0.34 ml. of diisopropylethylamine in 10 ml. of acetonitrile is shakenuntil completely miscible, then left standing one hour at about 25° C.The mixture is concentrated under reduced pressure to a crude residueand subjected to silica gel chromatography, eluting with ethyl acetateand then with acetonitrile. The residue obtained by concentration ofselected fractions, 0.682 g., is recrystallized from ethylacetate-hexane as the title compound, white free-flowing crystals 0.668g., m.p. 112.2°-113.2° C., having R_(f) 0.7 (TLC on silica gel in ethylacetate).

EXAMPLE 15 16,16-Dimethyl-PGE₁, p-Phenylphenacyl Ester (Formula VI-Cwherein M is ##STR44## X is trans--CH═CH--, and Y is --CH₂ CH₂ --)

Following the procedure of Example 14 but using 0.30 g. fo16,16-dimethyl-PGE₁, 0.75 g. of p-phenylphenacyl bromide, and 0.5 ml. ofdiisopropylethylamine in 12 ml. of acetonitrile, there is obtained acrude residue. This residue is subjected to silica gel chromatography,eluting with 33 to 60% ethyl acetate in Skellysolve B. The residueobtained by concentration of selected fractions, is crystallized fromethyl ether-Skellysolve B as the title compound, 0.175 g., free-flowingcrystals, m.p. 77°-8° C., having NMR peaks at 7.3-8.1, 5.66, 5.36,3.25-4.3, 0.9, and 0.85δ, and having R_(f) 0.60 (TLC on silica gel inethyl acetate).

EXAMPLE 16 17-Phenyl-18,19,20-trinor-PGE₁, p-Phenylphenacyl Ester(Formula VI-C wherein M is ##STR45## X is trans--CH═CH--, and Y is --CH₂CH₂ --)

Following the procedure of Example 14 but using 0.20 g. of17-phenyl-18,19,20-trinor-PGE₁, 0.6 g. of p-phenylphenacyl bromide, and0.4 ml. of diisopropylethylamine in 10 ml. of acetonitrile, there isobtained a crude solid residue. This residue is subjected to silica gelchromatography, eluting with 30-100% ethyl acetate in Skellysolve B. Theresidue obtained by concentration of selected fractions, 0.277 g.,partially crystalline, is recrystallized from acetone-Skellysolve B asthe title compound 0.18 g., white free-flowing needles, m.p. 112°-113°C., having R_(f) 0.53 (TLC on silica gel in ethyl acetate) and infraredabsorption bonds at 3360, 1745, 1715, 1685, 1600, 1240, 1165, 1125,1095, 1075, 1005, 970, 765, 750, 700, and 695 cm⁻¹.

EXAMPLE 17 13,14-Dihydro-PGE₁, p-Phenylphenacyl Ester (Formula VI-Cwherein M is ##STR46## Q is n-pentyl, and X and Y are --CH₂ CH₂ --)Following the procedure of Example 14 but using 2.7 g. of13,14-dihydro-PGE₁, 5.0 g. of p-phenylphenacyl bromide, and 4.5 ml. ofdiisopropylethylamine in 110 ml. of acetonitrile, there is obtained acrude residue. This residue is subjected to silica gel chromatography,eluting with 40-75% ethyl acetate in Skellysolve B. The residue obtainedby concentration of selected fractions, 3.2 g. is crystallized fromethyl acetate-Skellysolve B (1:3) as the title compound, 2.63 g., whitefree-flowing crystals, m.p. 89°-91° C., having infrared absorption bandsat 3420, 1745, 1725, 1690, 1605, 1580, 1555, 1485, 1340, 1235, and 1165.

Following the procedures of Examples 1-17 but employing the racemicforms of the PG compounds, there are obtained the corresponding estersof racemic PG compounds.

EXAMPLES 18-112

The phenacyl-type esters of PGE₂, PGE₁, 13,14-dihydro-PGE₁, and their15-methyl, 16-(or 16,16-di)methyl, or phenylsubstituted analogs,including the respective 15(R) epimers of Tables I-XV below are obtainedfollowing the procedures of Example 1, wherein the prostaglandincompound is reacted in the presence of diisopropylethylamine with theappropriate phenacyl halide reagent listed in the Table. The crudeproducts, obtained by concentration under reduced pressure, are purifiedby means described herein or known in the art, including partitioning,solvent extraction, washing, silica gel chromatography, trituration, orcrystallization.

Following the procedures of Examples 18--112 but employing the racemicforms of the PG compounds, there are obtained the corresponding estersof the racemic PG compounds.

Likewise following the procedures of Examples 61-112 but employing the15(R) forms of the PG compounds and their racemic forms, there areobtained the corresponding esters of the respective 15(R) PG compoundsand their forms.

                  TABLE I                                                         ______________________________________                                        Esters of 15(R)-PGE.sub.2                                                     (Refer to formula VI wherein                                                   ##STR47##                                                                    Q is n-pentyl,                                                                X is trans-CHCH                                                               and Y is cis-CHCH.)                                                                                     Product 15(R)-PGE.sub.2                             Example                                                                              Phenacyl Halide    ester of formula:                                   ______________________________________                                        18     phenacyl bromide   VI-A                                                19     p-bromophenacyl bromide                                                                          VI-B                                                20     p-phenylphenacyl bromide                                                                         VI-C                                                21     p-nitrophenacyl bromide                                                                          VI-D                                                22     p-benzamidophenacyl bromide                                                                      VI-E                                                23     2-bromo-2'-acetonaphthone                                                                        VI-F                                                24     2-bromo-1,3-diphenyl-1,3-                                                     propanedione       VI-G                                                ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Esters of 15(S)-15-Methyl-PGE.sub.2                                           (Refer to formula VI wherein                                                   ##STR48##                                                                    Q is n-pentyl,                                                                X is trans-CHCH,                                                              and Y is cis-CHCH.)                                                                                     Product 15(S)-15-                                                             Methyl -PGE.sub.2 ester                             Example                                                                              Phenacyl Halide    of formula:                                         ______________________________________                                        25     phenacyl bromide   VI-A                                                26     p-bromophenacyl bromide                                                                          VI-B                                                27     p-benzamidophenacyl bromide                                                                      VI-E                                                28     2-bromo-2'-acetonaphthone                                                                        VI-F                                                29     2-bromo-1,3-diphenyl-1,3-                                                                        VI-G                                                       propanedione                                                           ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Esters of 15(R)-15-Methyl-PGE.sub.2                                           (Refer to formula VI wherein                                                   ##STR49##                                                                    Q is n-pentyl,                                                                X is trans-CHCH,                                                              and Y is cis-CHCH.)                                                                                     Product 15(R)-15-                                                             methyl -PGE.sub.2 ester                             Example                                                                              Phenacyl Halide    of formula:                                         ______________________________________                                        30     phenacyl bromide      VI-A                                             31     p-bromophenacyl bromide                                                                             VI-B                                             32     p-phenylphenacyl bromide                                                                            VI-C                                             33     p-benzamidophenacyl bromide                                                                         VI-E                                             34     2-bromo-2'-acetonaphthone                                                                           VI-F                                             35     2-bromo-1,3-diphenyl-1,3-                                                                           VI-G                                                    propanedione                                                           ______________________________________                                    

                  TABLE IV                                                        ______________________________________                                        Esters of 16,16-dimethyl -PGE.sub.2                                           (Refer to formula VI wherein                                                   ##STR50##                                                                    Q is C(CH.sub.3).sub.2(CH.sub.2).sub.3CH.sub.3,                               X is trans-CHCH,                                                              and Y is cis-CHCH.)                                                                                     Product 16,16-di-                                                             methyl PGE.sub.2 ester                              Example                                                                              Phenacyl Halide    of formula:                                         ______________________________________                                        36     p-bromophenacyl bromide                                                                             VI-B                                             37     p-nitrophenacyl bromide                                                                             VI-D                                             38     p-benzamidophenacyl bromide                                                                         VI-E                                             39     2-bromo-2'-acetonaphthone                                                                           VI-F                                             40     2-bromo-1,3-diphenyl-1,3-                                                                           VI-G                                                    propanedione                                                           ______________________________________                                    

                  TABLE V                                                         ______________________________________                                        Esters of 15(R)-16,16-dimethyl-PGE.sub. 2                                     (Refer to formula VI wherein                                                   ##STR51##                                                                    Q is C(CH.sub.3).sub.2(CH.sub.2).sub.3CH.sub.3,                               X is trans-CHCH,                                                              and Y is cis-CHCH.)                                                                                     Product 15(R)-16,-                                                            16-dimethyl-PGE.sub. 2                              Example                                                                              Phenacyl Halide    ester of formula:                                   ______________________________________                                        41     phenacyl bromide      VI-A                                             42     p-bromophenacyl bromide                                                                             VI-B                                             43     p-phenylphenacyl bromide                                                                            VI-C                                             44     p-nitrophenacyl bromide                                                                             VI-D                                             45     p-benzamidophenacyl bromide                                                                         VI-E                                             46     2-bromo-2'-acetonaphthone                                                                           VI-F                                             47     2-bromo-1,3-diphenyl-1,3-                                                                           VI-G                                                    propanedione                                                           ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                        Esters of 17-Phenyl-18,19,20-trinor-PGE.sub.2                                 (Refer to formula VI wherein                                                   ##STR52##                                                                     ##STR53##                                                                    X is trans-CHCH,                                                              and Y is cis-CHCH.)                                                                                    Product 17-phenyl-                                   Ex-                      18,19,20-trinor-                                     ample Phenacyl Halide    PGE.sub.2 ester of formula:                          ______________________________________                                        48    Phenacyl bromide       VI-A                                             49    p-bromophenacyl bromide                                                                              VI-B                                             50    p-phenylphenacyl bromide                                                                             VI-C                                             51    p-benzamidophenacyl bromide                                                                          VI-E                                             52    2-bromo-2'-acetonaphthone                                                                            VI-F                                             53    2-bromo-1,3-diphenyl-1,3-                                                                            VI-G                                                   propanedione                                                            ______________________________________                                    

                  TABLE VII                                                       ______________________________________                                        Esters of 15(R)-17-Phenyl-18,19,20-trinor-PGE.sub.2                           (Refer to formula VI wherein                                                   ##STR54##                                                                     ##STR55##                                                                    X is trans-CHCH,                                                              and Y is cis-CHCH.)                                                                                    Product 15(R)-                                                                17-phenyl-18,19,20-                                  Ex-                      trinor-PGE.sub.2 ester                               ample Phenacyl Halide    of formula:                                          ______________________________________                                        54    phenacyl bromide       VI-A                                             55    p-bromophenacyl bromide                                                                              VI-B                                             56    p-phenylphenacyl bromide                                                                             VI-C                                             57    p-nitrophenacyl bromide                                                                              VI-D                                             58    p-benzamidophenyl bromide                                                                            VI-E                                             59    2-bromo-2'-acetonaphthone                                                                            VI-F                                             60    2-bromo-1,3-diphenyl-1,3-                                                                            VI-G                                                   propanedione                                                            ______________________________________                                    

                  TABLE VIII                                                      ______________________________________                                        Esters of PGE.sub.1                                                           (Refer to formula VI wherein                                                   ##STR56##                                                                    Q is n-pentyl,                                                                X is trans-CHCH,                                                              and Y is CH.sub.2 CH.sub.2.)                                                                            Product PGE.sub.1                                   Example                                                                              Phenacyl Halide    ester of formula:                                   ______________________________________                                        61     phenacyl bromide   VI-A                                                62     p-bromophenacyl bromide                                                                          VI-B                                                63     p-nitrophenacyl bromide                                                                          VI-D                                                64     p-benzamidophenacyl bromide                                                                      VI-E                                                65     2-bromo-2'-acetonaphthone                                                                        VI-F                                                66     2-bromo-1,3-diphenyl-1,3-                                                                        VI-G                                                       propanedione                                                           ______________________________________                                    

                  TABLE IX                                                        ______________________________________                                        Esters of 15(S)-15-Methyl-PGE.sub.1                                           (Refer to formula VI wherein                                                   ##STR57##                                                                    Q is n-pentyl,                                                                X is trans-CHCH                                                               and Y is CH.sub.2 CH.sub.2.)                                                                                 Product                                                                      15(S)-                                                                        15-methyl-                                                                    PGE.sub.1 ester                                 Example                                                                              Phenacyl Halide        of formula:                                     ______________________________________                                        67     phenacyl bromide       VI-A                                            68     p-bromophenacyl bromide                                                                              VI-B                                            69     p-phenylphenacyl bromide                                                                             VI-C                                            70     p-nitrophenacyl bromide                                                                              VI-D                                            71     p-benzamidophenacyl bromide                                                                          VI-E                                            72     2-bromo-2'-acetonaphthone                                                                            VI-F                                            73     2-bromo-1,3-diphenyl-1,3-propanedione                                                                VI-G                                            ______________________________________                                    

                  TABLE X                                                         ______________________________________                                        Esters of 16,16-Dimethyl-PGE.sub.1                                            (Refer to formula VI wherein                                                   ##STR58##                                                                    Q is C(CH.sub.3).sub.2(CH.sub.2).sub.3CH.sub.3,                               X is trans-CHCH,                                                              and Y is CH.sub.2 CH.sub.2.)                                                                                Product                                                                       16,16-di-                                                                     methyl-PGE.sub.1                                                              ester of                                        Example                                                                              Phenacyl Halide        formula:                                        ______________________________________                                        74     phenacyl bromide       VI-A                                            75     p-bromophenacyl bromide                                                                              VI-B                                            76     p-nitrophenacyl bromide                                                                              VI-D                                            77     p-benzamidophenacyl bromide                                                                          VI-E                                            78     2-bromo-2'-acetonaphthone                                                                            VI-F                                            79     2-bromo-1,3-diphenyl-1,3-propanedione                                                                VI-G                                            ______________________________________                                    

                  TABLE XI                                                        ______________________________________                                        Esters of 17-Phenyl-18,19,20-trinor-PGE.sub.1                                 (Refer to formula VI wherein                                                   ##STR59##                                                                     ##STR60##                                                                    X is trans-CHCH,                                                              and Y is CH.sub.2 CH.sub.2.)                                                                                Product                                                                       17-phenyl-                                                                    18,19,20-                                                                     trinor-PGE.sub.1                                                              ester of                                        Example                                                                              Phenacyl Halide        formula:                                        ______________________________________                                        80     phenacyl bromide       VI-A                                            81     p-bromophenacyl bromide                                                                              VI-B                                            82     p-nitrophenacyl bromide                                                                              VI-D                                            83     p-benzamidophenacyl bromide                                                                          VI-E                                            84     2-bromo-2'-acetonaphthone                                                                            VI-F                                            85     2-bromo-1,3-diphenyl-1,3-propanedione                                                                VI-G                                            ______________________________________                                    

                  TABLE XII                                                       ______________________________________                                        Esters of 13,14-Dihydro-PGE.sub.1                                             (Refer to formula VI wherein                                                   ##STR61##                                                                    Q is n-pentyl, and                                                            X and Y are CH.sub.2 CH.sub.2.)                                                                           Product                                                                       13,14-di-                                                                     hydro-PGE.sub.1 ester                             Example  Phenacyl Halide    of formula:                                       ______________________________________                                        86      phenacyl bromide    VI-A                                              87      p-bromophenacyl bromide                                                                           VI-B                                              88      p-nitrophenacyl bromide                                                                           VI-D                                              89      p-benzamidophenacyl bromide                                                                       VI-E                                              90      2-bromo-2'-acetonaphthone                                                                         VI-F                                              91      2-bromo-1,3-diphenyl-1,3-                                                                         VI-G                                                      propanedione                                                          ______________________________________                                    

                  TABLE XIII                                                      ______________________________________                                        Esters of 15(S)-15-Methyl-13,14-Dihydro-PGE.sub.1                             (Refer to formula VI wherein                                                   ##STR62##                                                                    Q is n-pentyl, and                                                            X and Y are CH.sub.2 CH.sub.2.)                                                                          Product                                                                       15(S)-15-methyl-                                                              13,14-dihydro-PGE.sub.1                            Example Phenacyl Halide    ester of formula:                                  ______________________________________                                        92      phenacyl bromide   VI-A                                               93      p-bromophenacyl bromide                                                                          VI-B                                               94      p-phenylphenacyl bromide                                                                         VI-C                                               95      p-nitrophenacyl bromide                                                                          VI-D                                               96      p-benzamidophenacyl bromide                                                                      VI-E                                               97      2-bromo-2'-acetonaphthone                                                                        VI-F                                               98      2-bromo-1,3-diphenyl-1,3-                                                                        VI-G                                                       propanedione                                                          ______________________________________                                    

                  TABLE XIV                                                       ______________________________________                                        Esters of 16,16-Dimethyl-13,14-dihydro-PGE.sub.1                              (Refer to formula VI wherein                                                   ##STR63##                                                                    Q is C(CH.sub.3).sub.2(CH.sub.2).sub.3CH.sub.3, and                           X and Y are CH.sub.2 CH.sub.2.)                                                                         Product 16,16-di-                                                             methyl-13,14-dihydro-                                                         PGE.sub.1 ester of                                  Example                                                                              Phenacyl Halide    formula:                                            ______________________________________                                         99    phenacyl bromide   VI-A                                                100    p-bromophenacyl bromide                                                                          VI-B                                                101    p-phenylphenacyl bromide                                                                         VI-C                                                102    p-nitrophenacyl bromide                                                                          VI-D                                                103    p-benzamidophenacyl bromide                                                                      VI-E                                                104    2-bromo-2'-acetonaphthone                                                                        VI-F                                                105    2-bromo-1,3-diphenyl-                                                                            VI-G                                                       1,3-propanedione                                                       ______________________________________                                    

                  TABLE XV                                                        ______________________________________                                        Esters of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGE.sub.1                   (Refer to formula VI wherein                                                   ##STR64##                                                                     ##STR65##                                                                    X and Y are CH.sub.2 CH.sub.2.)                                                                         Product                                                                       13,14-dihydro-                                                                17-phenyl-                                                                    18,19,20-trinor-PGE.sub.1                           Example                                                                              Phenacyl Halide    ester of formula:                                   ______________________________________                                        106    phenacyl bromide   VI-A                                                107    p-bromophenacyl bromide                                                                          VI-B                                                108    p-phenylphenacyl bromide                                                                         VI-C                                                109    p-nitrophenacyl bromide                                                                          VI-D                                                110    p-benzamidophenacyl bromide                                                                      VI-E                                                111    2-bromo-2'-acetonaphthone                                                                        VI-F                                                112    2-bromo-1,3-diphenyl-                                                                            VI-G                                                       1,3-propanedione                                                       ______________________________________                                    

I claim:
 1. An optically active compound of the formula: ##STR66##wherein each of R₄ and R₅ is hydrogen or methyl, being the same ordifferent; wherein M is ##STR67## wherein R₃ is hydrogen or methyl;wherein R₁ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl; wherein R₂ is hydrogen or benzoyl; andwherein(a) X is --CH₂ CH₂ -- or trans--CH═CH-- and Y is --CH₂ CH₂ --, or(b) X is trans--CH═CH-- and Y is cis--CH═CH--.
 2. A compound accordingto claim 1 wherein X is trans--CH═CH-- and Y is cis--CH═CH--.
 3. Acompound according to claim 2 wherein R₄ and R₅ are hydrogen.
 4. Acompound according to claim 3 wherein R₃ is hydrogen.
 5. The phenacylester of PGE₂, a compound according to claim
 4. 6. The p-bromophenacylester of PGE₂, a compound according to claim
 4. 7. The p-phenylphenacylester of PGE₂, a compound according to claim
 4. 8. The p-nitrophenacylester of PGE₂, a compound according to claim
 4. 9. Thep-benzamidophenacyl ester of PGE₂, a compound according to claim
 4. 10.The 2-naphthoylmethyl ester of PGE₂, a compound according to claim 4.11. The α-benzoylphenacyl ester of PGE₂, a compound according to claim4.
 12. A compound according to claim 3 wherein R₃ is methyl.
 13. Thep-phenylphenacyl ester of 15(S)-15-methyl-PGE₂, a compound according toclaim
 12. 14. The p-nitrophenacyl ester of 15(S)-15-methyl-PGE₂, acompound according to claim
 12. 15. The p-nitrophenacyl ester of15(R)-15-methyl-PGE₂, a compound according to claim
 12. 16. A compoundaccording to claim 2 wherein R₄ and R₅ are methyl.
 17. The phenacylester of 16,16-dimethyl-PGE₂, a compound according to claim
 16. 18. Thep-phenylphenacyl ester of 16,16-dimethyl-PGE₂, a compound according toclaim
 16. 19. A compound according to claim 1 wherein X istrans--CH═CH-- and Y is --CH₂ CH₂ --.
 20. A compound according to claim19 wherein R₄ and R₅ are hydrogen.
 21. The p-phenylphenacyl ester ofPGE₁, a compound according to claim
 22. 22. A compound according toclaim 19 wherein R₄ and R₅ are methyl.
 23. The p-phenylphenacyl ester of16,16-dimethyl-PGE₁, a compound according to claim
 22. 24. A compoundaccording to claim 1 wherein X and Y are --CH₂ CH₂ --.
 25. A compoundaccording to claim 24 wherein R₄ and R₅ are hydrogen.
 26. Thep-phenylphenacyl ester of 13,14-dihydro-PGE₁, a compound according toclaim
 25. 27. A compound according to claim 24 wherein R₄ and R₅ aremethyl.
 28. The p-phenylphenacyl ester of16,16-dimethyl-13,14-dihydro-PGE₁, a compound according to claim
 27. 29.Free-flowing crystals of a compound of the formula: ##STR68##
 30. Anoptically active compound of the formula ##STR69## wherein each of R₄and R₅ is hydrogen or methyl, being the same or different; wherein M is##STR70## wherein R₃ is hydrogen or methyl; wherein R₁ is phenyl,p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or2-naphthyl; and wherein (a) X is --CH₂ CH₂ -- or trans--CH═CH-- and Y is--CH₂ CH₂ --, or (b) X is trans--CH═CH-- and Y is cis--CH═CH--.